Benzo f!quinoxalinedione derivatives, their production and use in pharmaceutical agents

ABSTRACT

Compounds of formula I ##STR1## are described, in which substituents R 1  -R 4  have the meanings mentioned in the application as well as their production and use in pharmaceutical agents.

This is a 371 of PCT/DE94/00495, filed Apr. 28, 1994.

The invention relates to benzo f!quinoxalinedione derivatives, theirproduction and use in pharmaceutical agents.

It is known that quinoxaline derivatives have an affinity to thequisqualate receptors and, because of this receptor binding, aresuitable as pharmaceutical agents for the treatment of diseases of thecentral nervous system.

The compounds according to the invention have formula I ##STR2## inwhich

R¹ and R⁴ are the same or different and mean hydrogen, C₁₋₁₂ alkylsubstituted with R², C₂₋₁₂ alkenyl substituted with R², C₂₋₁₂ alkynylsubstituted with R², C₃₋₇ cycloalkyl substituted with R², --(CH₂)_(n)--C₆₋₁₂ aryl, which is substituted with R² in the aryl or in the alkylradical or --(CH₂)_(n) -hetaryl, which is substituted with R² in thehetaryl or alkyl radical, and R¹ and R⁴ do not mean hydrogen at the sametime,

R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are the same or different and mean hydrogen,halogen, nitro, NR¹⁶ R¹⁷, NHCOR¹¹, SO₀₋₃ R¹², C₃₋₇ cycloalkyloxy, COR¹³,cyano, CF₃, OCH₂ CF₃, C₁₋₆ alkyl or C₁₋₄ alkoxy, and

R² is --CN, -tetrazole, --C(NOH)NH2, --CO--R³ or --PO-XY and R² is thesame or different in one to two places, and

n is 0, 1, 2, 3, 4 or 5,

R³ means hydroxy, C₁₋₆ alkoxy or NR¹⁴ R¹⁵,

X and Y are the same or different and mean hydroxy, C₁₋₆ alkoxy,--O--(CH₂)_(p) --O--, C₁₋₄ alkyl or NR¹⁴ R¹⁵ and p is 1, 2 or 3, and

R¹¹ means C₁₋₆ alkyl or phenyl, which can be substituted with halogen,

R¹² means hydrogen, C₁₋₄ alkyl, NH₂, N(C₁₋₄ alkyl)₂, --NH(C₁₋₄ alkyl)--NH--CH₂ CONH₂, --CH₂ CONH₂, CF₃ or --NH--(CH₂)_(n) --R² and

R¹³ means hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkyl or NR¹⁴ R¹⁵,

R¹⁴ and R¹⁵, R¹⁶ and R¹⁷ are the same or different and mean hydrogen,--CO--C₁₋₆ alkyl, phenyl or C₁₋₆ alkyl, which optionally can besubstituted with C₁₋₄ alkoxy or with an amino group that is optionallymono- or disubstituted with C₁₋₄ alkyl, or together with the nitrogenatom can form a 5- to 7-membered saturated heterocycle, which cancontain another N, S or O atom and can be substituted or can form anunsaturated 5-membered heterocycle, which can contain 1-3N atoms and canbe substituted,

as well as their isomers or salts, and, if R⁵ -R¹⁰ is hydrogen, R¹ or R⁴does not mean methanephosphonic acid or ethane-1-phosphonic acid.

The compounds of general formula I also contain the possible tautomericforms and comprise the E or Z isomers or, if a chiral center is present,the racemates or enantiomers.

The substituents are preferably in 6- and/or 7-position.

Substituent R² appears in one to two places, the same or different inany position on the alkyl, alkenyl, alkynyl, cycloalkyl, hetaryl, arylor (CH₂)_(n) radical.

Alkyl is to be understood to mean respectively a straight-chain orbranched alkyl radical, such as, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, heptyl,octyl, nonyl, decyl, and C₁₋₆ alkyl radicals are preferred.

Alkenyl especially comprises C₂₋₆ alkenyl radicals, which can bestraight-chain or branched, such as, for example, 2-propenyl, 2-butenyl,3-methyl-2-propenyl, 1-propenyl, 1-butenyl, vinyl.

Ethynyl, 1-propynyl, 2-propynyl, 1-butynyl with 2-4 carbon atoms areespecially suitable as alkynyl radicals.

By C₃₋₇ cycloalkyl is meant respectively cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, especially C₃₋₅ cycloalkyl.

As aryl radical, for example, phenyl, naphthyl, biphenyl and indenyl,especially (CH₂)_(n) -phenyl with n=0, 1 or 2, are mentioned.

As hetaryl radical, 5- or 6-membered heteroaromatic substances with 1-3nitrogen atoms, such as, for example, pyrazole, imidazole, pyrazine,pyridine, pyrimidine, pyridazine, triazine, are suitable.

Halogen is to be understood to mean respectively fluorine, chlorine,bromine and iodine, especially fluorine, chlorine and bromine.

If R¹⁴, R¹⁵ and R¹⁶, R¹⁷ together with the nitrogen atom form asaturated heterocycle, then, for example, piperidine, pyrrolidine,morpholine, thiomorpholine, hexahydroazepine or piperazine are meant. Assubstituents of the heterocycle, C₁₋₄ alkyl groups can be mentioned,such as N-methyl-piperazine, 2,6-dimethylmorpholine or aryl groups suchas phenylpiperazine. The substituent can appear in one to three places.

If R¹⁴, R¹⁵ and R¹⁶, R¹⁷ together with the nitrogen atom form anunsaturated heterocycle, then, for example, imidazole, pyrazole, pyrroleand triazole can be mentioned, which can be substituted in one to twoplaces with cyano, C₁₋₄ alkyl, phenyl or CO₂ C₁₋₆ alkyl.

Preferred are compounds with R² meaning --COR³ or --POXY and R¹ /R⁴meaning alkyl.

The physiologically compatible salts of organic and inorganic bases aresuitable as salts, such as, for example, the readily soluble alkali andalkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine,sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol,Sovak base, 1-amino-2,3,4-butanetriol.

If a basic function is contained, the physiologically compatible saltsof organic and inorganic acids are suitable, such as HCl, H₂ SO₄,phosphoric acid, citric acid, tartaric acid, i.a.

The compounds of formula I as well as their physiologically compatiblesalts can be used as pharmaceutical agents because of their affinity tothe AMPA or Kainat receptors. Because of their action profile, thecompounds according to the invention are suitable for the treatment ofdiseases that are caused by hyperactivity of excitatory amino acids,such as, for example, glutamate or aspartate. Since the new compoundsact as antagonists of excitatory amino acids and show a high specificaffinity to the AMPA receptors, by displacing the radioactively-labeledspecific agonist (RS)α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate(AMPA) from the AMPA receptors, they are especially suitable for thetreatment of those diseases that are affected by the receptors ofexcitatory amino acids, especially the AMPA receptor, such as for thetreatment of neurological and psychiatric diseases. The neurologicaldiseases that can be treated functionally and preventatively include,for example, neurodegenerative disorders, such as, Parkinson's disease,Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosisand olivopontocerebellar degeneration. According to the invention, thecompounds can be used for the prevention of postischemic celldestruction, cell destruction after cerebral trauma, in the case of astroke, hypoxia, anoxia and hypoglycemia and for the treatment of seniledementia, multiinfarct dementia as well as epilepsy and muscle spasms.The psychiatric diseases include anxiety conditions, schizophrenia,migraine, conditions of pain, as well as the treatment of sleepdisorders or the withdrawal symptoms after drug abuse such as in thecase of alcohol, cocaine, benzodiazepine or opiate withdrawal.

For use of the compounds according to the invention as pharmaceuticalagents, the latter are brought into the form of a pharmaceuticalpreparation, which contains, besides the active ingredient for enteralor parenteral administration, suitable pharmaceutical, organic orinorganic inert vehicles, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkyleneglycols, etc. The pharmaceutical preparations can be insolid form, for example, as tablets, coated tablets, suppositories,capsules or in liquid form, for example, as solutions, suspensions oremulsions. Moreover, they optionally contain adjuvants such aspreservatives, stabilizers, wetting agents or emulsifiers, salts forchanging the osmotic pressure or buffers.

Especially suitable for parenteral use are injection solutions orsuspensions, in particular aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil.

Surface-active adjuvants such as salts of bile acids or animal orvegetable phospholipids, but also their mixtures as well as liposomes ortheir components can be used as vehicle systems.

Especially suitable for oral use are tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binders, such as, for example,lactose, corn or potato starch. The use can even take place in liquidform, such as, for example, as juice, to which a sweetener is optionallyadded.

The dosage of the active ingredients can vary depending on method ofadministration, age and weight of the patient, type and severity of thedisease to be treated and similar factors. The daily dose is 0.5-1000mg, preferably 50-200 mg, and the dose can be administered as a singledose to be administered once or subdivided into 2 or more daily doses.

The production of the compounds according to the invention takes placeaccording to methods known in the art. For example, compounds of formulaI are achieved in that

a) a compound of formula II or III ##STR3## in which R¹ to R¹⁰ have theabove-mentioned meaning, is cyclized with oxalic acid or reactive oxalicacid derivatives or

b) a compound of formula IV or V ##STR4## in which R¹ to R¹⁰ have theabove-mentioned meaning, is reacted with oxalic acid or reactive oxalicacid derivatives and after reduction of the nitro group is cyclized or

c) a compound of formula VI ##STR5## in which R⁵ to R¹⁰ have theabove-mentioned meaning is reacted in the presence of a base with R¹ Zor R⁴ Z, in which Z represents a leaving group, and then optionally theester group is saponified or the acid group is esterified or amidated orthe nitro group is reduced to the amino group or the amino group isalkylated or acylated or the amino group is exchanged for halogen orcyano or a nitro group or halogen is introduced or a nitrile isconverted into the tetrazole or amidoxime or nucleophilicallysubstituted or the isomers are separated or the salts are formed.

The cyclization of the compounds of formulas II and III takes place inone stage or else in two stages with oxalic acid or a reactive oxalicacid derivative. Regarded as preferable is the two-stage process, inwhich the diamine is reacted with an oxalic acid derivative such asoxalic ester semi-chloride or reactive oxalic acid imidazolidederivatives in polar solvents such as cyclic or acyclic ethers orhalogenated hydrocarbons, for example, tetrahydrofuran, diethyl ether ormethylene chloride in the presence of a base such as organic amines, forexample, triethylamine, pyridine, Hunig base or diethylaminopyridine.The subsequent cyclization can be performed in a basic or else acidicmanner, but preferably in an acid environment, and alcohol can be addedto the solvent.

Alkali hydrides, such as NaH, that are used in inert solvents, forexample, hydrocarbons and ethers such as dimethoxyethane, THF, i.a.,also represent suitable bases for the two-stage process.

In process variant b), after the acylation with oxalic acid or thereactive oxalic acid derivative, in the usual way, the nitro group isreduced catalytically or by reduction with iron powder in acetic acid athigher temperatures or else with sodium sulfide and ammonium hydroxidein alcohol and is cyclized as described above.

The introduction of substituents R¹ and R⁴ takes place according toprocess c) according to usual alkylation methods by reacting thequinoxalinedione with R¹ - or R⁴ -Z, in which Z, for example, meanstosylate, mesylate, triflate, nonaflate or halogen, in the presence ofbases at room temperature or higher temperature in aprotic solvents. Theanion can also be produced before R¹ - or R⁴ -Z is added. As bases, forexample, alkali compounds such as potassium carbonate, sodium hydroxide,alkali alcoholates and especially metal hydrides such as sodium hydrideare suitable. Optionally, the alkali compounds can also be reacted underphase transfer conditions. If mixtures of compounds with substituent R¹or R⁴ are obtained, they are separated in the usual way. Aprotic polarsolvents, such as dimethylformamide, N-methylpyrrolidone, but alsocyclic ethers, such as dioxane or tetrahydrofuran, are suitable solventsfor the reaction.

If the reaction takes place in process variant c) with 2 mol of R¹ -Zunder otherwise analogous reaction conditions, then substituents R¹ andR⁴ are introduced at the same time.

The optionally subsequent saponification of an ester group can takeplace in a basic or preferably acidic manner, by hydrolyzing thereaction mixture at a higher temperature up to the boiling temperaturein the presence of acids such as highly concentrated aqueoushydrochloric acid in solvents, such as, for example, trifluoroaceticacid or alcohols. Phosphonic acid esters are preferably hydrolyzed byheating in highly concentrated aqueous acids, such as, for example,concentrated hydrochloric acid or by treatment with a trimethylsilylhalide and subsequent treatment with water.

The esterification of the carboxylic acid or phosphonic acid takes placein a way known in the art with the corresponding alcohol in acid or inthe presence of an activated acid derivative. As activated acidderivatives, for example, acid chloride, acid imidazolide or acidanhydride are suitable. In the case of the phosphonic acids, theesterification can be achieved by reaction with orthoesters, optionallywith addition of catalysts such as p-toluenesulfonic acid.

The amidation takes place on the free acids or on their reactivederivatives, such as, for example, acid chlorides, mixed anhydrides,imidazolides or azides by reaction with the corresponding amines at roomtemperature.

The reduction of the nitro group to the amino group takes placecatalytically in polar solvents at room temperature or a highertemperature under hydrogen pressure. Metals such as Raney nickel ornoble metal catalysts such as palladium or platinum, optionally in thepresence of barium sulfate or on vehicles, are suitable as catalysts.Instead of hydrogen, ammonium formate can also be used in a known way.Reducing agents such as tin(II)chloride or titanium(III)chloride can beused just as complex metal hydrides possibly in the presence of heavymetal salts. It can be advantageous to introduce the ester group beforethe reduction. Nitro groups can also be selectively reduced with Na₂ Sor sodium dithionite in the usual way.

If an alkylation of an amino group is desired, alkylation can beperformed according to usual methods, for example, with alkyl halides oraccording to the Mitsonubo variant by reaction with an alcohol in thepresence of triphenylphosphine and azodicarboxylic acid ester or theamine can be subjected to a reductive amination with aldehydes orketones optionally in succession with two different carbonyl compounds,and mixed derivatives are obtained (literature, e.g., Verardo et al.,Synthesis 1993, 121; Synthesis 1991, 447; Kawaguchi, Synthesis 1985,701; Micovic et al. Synthesis 1991, 1043).

The acylation of an amino group takes place in the usual way, forexample, with an acid halide or acid anhydride optionally in thepresence of a base such as dimethylaminopyridine in solvents such asmethylene chloride, tetrahydrofuran or pyridine or according to theScotten Baumann reaction.

The introduction of the cyano group can take place with the help of theSandmeyer reaction; for example, the diazonium salts, intermediatelyformed from the amino compounds with nitrites, can be reacted withalkali cyanides in the presence of Cu--I-cyanide.

The introduction of the halogens chlorine, bromine or iodine by theamino group can take place, for example, also according to Sandmeyer, bythe diazonium salts formed intermediately with nitrites being reactedwith Cu(I)chloride or Cu(I)bromide in the presence of the correspondingacid such as hydrochloric acid or hydrobromic acid or with potassiumiodide.

If an organic nitrous acid ester is used, the halogens can beintroduced, e.g., with addition of methylene iodide or tetrabromomethanein a solvent such as, for example, dimethylformamide.

The introduction of fluorine is possible, for example, by Balz Schiemannreaction of the diazonium tetrafluoroborate.

The introduction of an NO₂ group is possible by a series of knownnitration methods. For example, nitration can be performed withnitronium tetrafluoroborate in inert solvents, such as halogenatedhydrocarbons or in sulfolane, glacial acetic acid or acetonitrile. Theintroduction is also possible, e.g., by nitrating acid in water orconcentrated sulfuric acid as solvent at temperatures between 0° C. and30° C.

The introduction of halogen is possible by known halogenation methods,such as, e.g., by electrophilic aromatic substitution.

For example, iodization can be performed according to a process withiodine and iodic acid of Wirth et al. Liebigs Ann. Chem. 634, 84 (1960)!or with N-iodosuccinimide in solvents such as tetrahydrofuran,dimethylformamide or trifluoromethane sulfonic acid.

The introduction of the tetrazole is made possible by reaction of thecorresponding nitrile with an azide such as, e.g., trimethylsilyl azide,hydrazoic acid or sodium azide, optionally with addition of a protonsource, such as, e.g., ammonium chloride or triethylammonium chloride inpolar solvents such as dimethylformamide, dimethylacetamide orN-methylpyrrolidone at temperatures up to boiling point of the solvent.

Amidoximes are produced from the corresponding nitrile withhydroxylamine hydrochloride, for example, in alcohol-water mixtures, assolvent.

The nucleophilic substitution is performed according to methods known inthe literature in the presence of a base and is fostered by anactivating electron-attracting group such as, e.g., nitro, cyano,trifluoromethyl, preferably in o-position. As nucleophiles, for example,primary and secondary amines, N-containing unsaturated and saturatedheterocycles, cyanide, alcoholates, thiolates, i.a., are suitable. Thereaction can be performed in polar solvents such as alcohols,halogenated hydrocarbons, dimethylacetamide, acetonitrile or water orwithout solvents. As bases, inorganic bases such as alkali oralkaline-earth hydroxides or carbonates or organic bases such as cyclic,acyclic and aromatic amines, such as DBU, Hunig base, pyridine ordimethylaminopyridine are suitable. In the case of amines, thenucleophile itself can be used in excess as base and optionally it ispossible to work without any further solvent. For example, the activatedsulfonic acid derivative, such as sulfonic acid chloride, can be reactedin the usual way with nucleophilic N derivatives (such as H₂ N(C₁₋₄alkyl) or H₂ N--CH₂ CONH₂ or H₂ N--CH₂ --R²) or with nucleophlic Cderivatives (such as CF₃ anion or CH₂ --CONH₂ anion).

The mixtures of isomers can be separated according to usual methods suchas, for example, crystallization, chromatography or salt formation inthe enantiomers and E/Z isomers.

The production of the salts takes place in the usual way, by mixing asolution of the compound of formula I with the equivalent amount or anexcess of an alkali or alkaline-earth compound, which optionally is insolution, and the precipitate being separated or the solution beingworked up in the usual way.

If the production of the starting compounds is not described, the latterare known or can be produced analogously to known compounds, such as,for example, according to WO 93/08171 or according to processesdescribed here.

The following processes are to explain the production of the compoundsaccording to the invention:

EXAMPLE 1 (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

The synthesis of 2,4-dinitro-1-fluorophthaline takes place as describedin the literature: J. Chem. Soc. 1962, 2616

The synthesis of 2,4-dinitro-1-chloronaphthalene takes place asdescribed in the literature: Reports 1908, 41, 3932

The synthesis of toluenesulfonic acid-(2,4-dinitronaphth-1-ol)-estertakes place as described in the literature: Reports 1908, 41, 3932

a) Trifluoromethanesulfonic acid-(2,4-dinitronaphth-1-ol)-ester

2 g of 2,4-dinitronaphth-1-ol (Martius yellow) is mixed in 30 ml ofdichloromethane with 1.72 ml=1.2 equivalents of trifluoromethanesulfonicanhydride and 1.43 ml of triethylamine and stirred at room temperatureuntil the feedstock disappears. It is diluted with dichloromethane,neutralized, washed with brine and the solvent is removed. The crudeproduct is recrystallized from hot ethanol. 89% of product is obtained.

Analogously, there is produced from nonafluorobutanesulfonyl fluoride intoluene:

Nonafluorobutanesulfonic acid-(2,4-dinitronaphth-1-ol)-ester

b) (2,4 Dinitro-1-naphthylamino)-methanephosphonic acid diethyl ester

4 g of 2,4 dinitro-1-chloronaphthalene (15.84 mmol) is dissolved in 6.5g of aminomethanephosphonic acid diethyl ester and 4 g ofdiphenylmethane and stirred for 72 hours at room temperature. The batchis diluted with methylene chloride, washed with 1N NaOH and washed twicewith brine, dried and spun in. The crude product is chromatographed onsilica gel with 3.5 liters of cyclohexane and ethyl acetate 1:1 asmobile solvent. 68% of product is obtained in several fractions asviscous oil. NMR (DMSO, delta in ppm): 1.15(6H,tr), 4(4H dq)4.25 (2H m),7.8, 7.98, 8.9, 9.05 each 1H, 8.6 (2H,d)

Produced in the same way are:

1-Phenyl-1-(2,4 dinitro-1-naphthylamino)-methanephosphonic acid diethylester

1-(2,4 dinitro-1-naphthylamino)-ethane-1-phosphonic acid diethyl ester

1-(2,4 dinitro-1-naphthylamino)-propane-1-phosphonic acid diethyl ester

1-(2,4 dinitro-1-naphthylamino)-butane-1-phosphonic acid diethyl ester

1-(2,4 dinitro-1-naphthylamino)-hexane-1-phosphonic acid diethyl ester

c) (2-Amino-4-nitro-1-naphthylamino)-methanephosphonic acid diethylester

1.352 g of (2,4 dinitro-1-naphthylamino)-methanephosphonic acid diethylester is dissolved in 32 ml of ethanol and 23 ml of water, to it isadded 4.4 ml of 25% ammonium hydroxide solution, 1.61 g of ammoniumchloride and 2.81 g of 35% sodium sulfide and the solution is heated fora few hours to 90° C. The ethanol-water mixture is concentrated byevaporation on a rotary evaporator, taken up in water, extracted withethyl acetate, washed with brine, dried and spun in. The crude productis chromatographed on silica gel with 2 liters of cyclohexane and ethylacetate 1:1 and 1 liter of pure ethyl acetate as mobile solvent. 262 mgof product is obtained in several fractions as brown solid.

Produced in the same way are:

1-(2-Amino-4-nitro-1-naphthylamino)-ethane-1-phosphonic acid diethylester

1-(2-amino-4-nitro-1-naphthylamino)-butane-1-phosphonic acid diethylester

1-(2-amino-4-nitro-1-naphthylamino)-hexane-1-phosphonic acid diethylester

1-phenyl-1-(2-amino-4-nitro-1-naphthylamino)-methanephosphonic aciddiethyl ester

1-(2-amino-4-nitro-1-naphthylamino)-propane-1-phosphonic acid diethylester (79% yield)

d) (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester

100 mg of (2-amino-4-nitro-1-naphthylamino)-methanephosphonic aciddiethyl ester is dissolved in a few ml of tetrahydrofuran and treatedwith 95 microliters of distilled ethyloxalyl chloride and 118microliters of triethylamine at ice-bath temperature. The solution isstirred first to room temperature and then the reaction is allowed to becompleted at 55° oil bath temperature. The batch is concentrated byevaporation, taken up in ethyl acetate and washed with brine, dried andspun in. The crude product is chromatographed on silica gel with ethanolas mobile solvent. 76 mg or 67% of theory of product is obtained aspolar fraction. NMR (DMSO,Delta in ppm): 1.03 (6H tr), 3.8 (4H dq), 4.93(2H d), 7.73 (2H dd), 8.2, 8.35, 8.47 each 1H.

Produced in the same way are:

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid diethyl ester of meltingpoint >300° (decomposition)

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-propane-1-phosphonic acid diethyl ester of meltingpoint >300° (decomposition)

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-butane-1-phosphonic acid diethyl ester

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-hexane-1-phosphonic acid diethyl ester

1-phenyl-1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester

e) (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

32 mg of (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester is introduced in2 ml of acetonitrile under nitrogen at room temperature. 80 microlitersof trimethylsilylbromide is instilled with a syringe. The solution isstirred for 20 hours at room temperature and concentrated byevaporation. The residue is suspended in a little water, suctioned offand washed with water. After drying of the crude product, 21 mg ofphosphonic acid is obtained. NMR (DMSO,Delta in ppm): 4.7 (2H d), 7.65(2H m), 8.2 (1H, m) 8.44 (2H). Melting point >340°

In a corresponding way, there are produced:

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid with melting point >300° C.

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-propane-1-phosphonic acid with melting point >300° C.

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-butane-1-phosphonic acid

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-hexane-1-phosphonic acid

1-phenyl-1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

EXAMPLE 2 1-(2,4 Dinitro-1-naphth-yl-N-ethoxyoxalyl!amino)-propane-1-phosphonic acid diethyl ester

A total of 1.2 mmol of triethylamine as well as 1.2 mmol of ethyl oxalylchloride are added little by little to 100 mg (0.24 mmol) of 1-(2,4dinitro-1-naphthylamino)-propane-1-phosphonic acid diethyl ester in 1.5ml of tetrahydrofuran and stirred for a total of 20 hours at 80° oilbath temperature. The solvent is concentrated by evaporation, the crudeproduct is divided between water and a lot of ethyl acetate, the organicphase is washed with brine, dried and spun in. The mixture that isproduced is chromatographed on silica gel with ethyl acetate as mobilesolvent. 24 mg of product as well as some feedstock is obtained as polarfraction.

Analogously, 2,4 dinitro-1-naphth-yl-N-ethoxyoxalyl!aminomethanephosphonic acid diethyl ester is produced.

EXAMPLE 3 (6,10-Dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

a) (6,10-Dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester

90 mg of (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester is dissolved in1 ml of methylene chloride and stirred with 30 mg of nitroniumtetrafluoroborate at ice bath temperature and later at room temperature.

It is adjusted to pH 8 with sodium bicarbonate solution, the organicphase is washed with brine, dried and spun in. The mixture that isproduced is chromatographed on silica gel. 24 mg of product is obtained.

Analogously, 1-(6,10-Dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid diethyl ester is produced.

b) In an analogous performance, the ester is saponified as described inExample 1e).

(6,10-Dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid and analogously

1-(6,10-dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid are obtained.

EXAMPLE 4 (6-Nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid and(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

a) 2-Nitro-5-sulfonamido-naphth-1-ol and 2,4dinitro-5-sulfonamido-naphth-1-ol

1 g of 5-sulfonamidonaphth-1-ol is nitrated with a mixture of nitricacid and water with ice bath cooling. The mixture is neutralized withsolid sodium bicarbonate, extracted with a lot of methylene chloride,washed with brine, dried and spun in. The mixture that is produced ischromatographed on silica gel. A mixture of2-nitro-5-sulfonamido-naphth-1-ol and 2,4dinitro-5-sulfonamido-naphth-1-ol results. NMR (DMSO,Delta in ppm): 7.8(4H m), 8.2 (2H m), 8.4 (1H, d), 8.7 (1H d) and 7.05 (2H s), 7.6 (1Hdd), 8.3 (1H d), 8.5 (1H, d) 8.8 (1H s) for the dinitronaphthol.

b) The toluenesulfonic acid esters are produced in an analogousperformance as described in the literature.

There are obtained

Toluenesulfonic acid-(2,4 dinitro-5-sulfonamido-naphth-1-ol)-ester aswell as

toluenesulfonic acid-(2-nitro-5-sulfonamido-naphth-1-ol)-ester.

c) The esters are reacted with aminoalkanephosphonic acid diethyl estersin an analogous performance as described in Example 1b). Thus producedare

1-Phenyl-1-(2,4 dinitro-5-sulfamoyl-1-naphthylamino)-methanephosphonicacid diethyl ester

1-methyl-1-(2,4 dinitro-5-sulfamoyl-1-naphthylamino)-ethane-1-phosphonicacid diethyl ester

(2,4 dinitro-5-sulfamoyl-1-naphthylamino)-methanephosphonic acid diethylester

1-(2,4 dinitro-5-sulfamoyl-1-naphthylamino)-propane-1-phosphonic aciddiethyl ester or

1-phenyl-1-(2-nitro-5-sulfamoyl-1-naphthylamino)-methanephosphonic aciddiethyl ester

1-methyl-1-(2-nitro-5-sulfamoyl-1-naphthylamino)-ethane-1-phosphonicacid diethyl ester

(2-nitro-5-sulfamoyl-1-naphthylamino)-methanephosphonic acid diethylester

1-(2-nitro-5-sulfamoyl-1-naphthylamino)-propane-1-phosphonic aciddiethyl ester

d) With the same methods as described in Example 1c), there are obtained

1-Phenyl-1-(2-amino-4-nitro-5-sulfamoyl-1-naphthylamino)-methanephosphonicacid diethyl ester

1-methyl-1-(2-amino-4-nitro-5-sulfamoyl-1-naphthylamino)-ethane-1-phosphonicacid diethyl ester

(2-amino-4-nitro-5-sulfamoyl-1-naphthylamino)-methanephosphonic aciddiethyl ester

1-(2-amino-4-nitro-5-sulfamoyl-1-naphthylamino)-propane-1-phosphonicacid diethyl ester or

1-phenyl-1-(2-amino-5-sulfamoyl-1-naphthylamino)-methanephosphonic aciddiethyl ester

1-methyl-1-(2-amino-5-sulfamoyl-1-naphthylamino)-ethane-1-phosphonicacid diethyl ester

(2-amino-5-sulfamoyl-1-naphthylamino)-methanephosphonic acid diethylester

1-(2-amino-5-sulfamoyl-1-naphthylamino)-propane-1-phosphonic aciddiethyl ester

e) By reaction with reactive oxalic acid derivatives as described, e.g.,in Example 1d) or according to known processes, there are produced

1-(6-Nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid diethyl ester

1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-propane-1-phosphonic acid diethyl ester

1-phenyl-1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester

(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester as well as

1-(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid diethyl ester

1-(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-propane-1-phosphonic acid diethyl ester

1-phenyl-1-(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester

(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester

f) The ester is saponified in an analogous performance as described inExample 1e). There are obtained

1-(6-Nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid

1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-propane-1-phosphonic acid

1-phenyl-1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid as well as

1-(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid

1-(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-propane-1-phosphonic acid

1-phenyl-1-(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

EXAMPLE 5

(6-Nitro-9-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid from purchased flavianic acid(5,7-dinitro-8-hydroxy-naphthalene-2-sulfonic acid) is producedanalogously after protection of the sulfonic acid.

EXAMPLE 6

1-(6-Nitro-9-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-phosphonic acid from purchased flavianicacid (5,7-dinitro-8-hydroxy-naphthalene-2-sulfonic acid) is producedanalogously to Example 5.

EXAMPLE 7 (6-Amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid from(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid

a) 0.3 mmol of (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester in 10 ml of DMFz.A. is dissolved, and 10 mg of platinum oxide catalyst, which waspreviously saturated with hydrogen, is added. It is hydrogenated withhydrogen for three hours at normal pressure and room temperature. Thecatalyst is suctioned off on Celite, the mother liquor is diluted withwater and the precipitate that is produced is suctioned off. 44% oftheory of (6-amino-2,3-dioxo-1,2,3,4-tetrahydro-benzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained. Thelatter is described as in Example 1e) or saponified according tostandard conditions with HCl to(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid (or to its hydrochloride,respectively).

Analogously, there is produced(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid.

b) With use of palladium/barium sulfate catalyst, there are producedanalogously:

1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetonitrile from1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetonitrile and

1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin--yl)-acetonitrile from1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-acetonitrile

EXAMPLE 8

(6-Cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained from(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid ester by diazotization andSandmeyer reaction with copper(I)cyanide. After saponification of theester with known methods, (6-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzo-f!quinoxalin-1-yl)-methanephosphonic acid is obtained.

Analogously, (6-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid is obtained from(6-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester.

EXAMPLE 9 (6-Nitro-7-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and(6-nitro-7-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

150 mg of 6-nitro-7-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxaline, which can be synthesized according to known methods, isdissolved in 1 ml of dimethylsulfoxide z.A. and 10 equivalents oftrifluoromethanesulfonylmethanephosphonic acid diethyl ester, which isproduced from the available alcohol 1-hydroxymethanephosphonic aciddiethyl ester according to standard methods, is added. After heating themixture to 160°, it is worked up for several hours. It is diluted withsodium bicarbonate solution, extracted with methylene chloride, driedand concentrated by evaporation. The crude product is chromatographed onsilica gel with ethyl acetate and then ethanol.

A base for bonding the trifluoromethanesulfonic acid is optionally addedin performing the process.

The new compounds obtained are

(6-Nitro-7-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester as well as

(6-nitro-7-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester.

Produced in the same way are:

(6-Nitro-8-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and

(6-nitro-8-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

(6-nitro-8,10-disulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and(6-nitro-8,10-disulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

(6-nitro-7-sulfonylmethano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and(6-nitro-7-sulfonylmethano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

(6-nitro-7-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and

(6-nitro-7-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

(6-nitro-8-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and(6-nitro-8-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

(6-nitro-7-bromo-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and(6-nitro-7-bromo-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

(6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid diethyl ester and(6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

EXAMPLE 10 (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid

The synthesis of 1-nitro-2-fluoronaphthalene takes place as described inthe literature.

The synthesis of 1-nitro-2-chloronaphthalene takes place as described inthe literature.

1-Nitro-2-hydroxynaphthalene can be purchased or produced by oxidationof nitroso-2-hydroxynaphthalene.

a) Toluenesulfonic acid-(1-nitronaphth-2-ol)-ester

5 g of 1-nitronaphth-1-ol is dissolved in 30 ml of triethylamine with5.54 g=1.1 equivalents of toluenesulfonic acid chloride at 60° andstirred at this temperature until the feedstock disappears. The mixtureis allowed to cool, is suctioned off and the precipitate is washed withcold ethanol. The crude product is recrystallized from hot ethylacetate. 9.1 g of product is obtained. NMR(DMSO): 2.44 (3H s), 7.5 (3Hd), 7.8 (5H,m) 8.17 (1H m), 8.34 (1H d).

Produced in a known way:

Nonafluorobutanesulfonic acid-(1-nitronaphth-2-ol)-estertrifluoromethanesulfonic acid-(1-nitronaphth-2-ol)-ester methanesulfonicacid-(1-nitronaphth-2-ol)-ester

b) (1-Nitro-2-naphthylamino)-methanephosphonic acid diethyl ester

450 mg of toluenesulfonic acid-(1-nitronaphth-2-ol)-ester is dissolvedin 436 mg of aminomethanephosphonic acid diethyl ester and 0.6 g ofdiphenylmethane and stirred for 72 hours at 40°-60°. The batch isdiluted with methylene chloride, washed with 1N NaOH and twice withbrine, dried and spun in. The crude product is chromatographed on silicagel with hexane and ethyl acetate 1:1 as mobile solvent. In addition to60% feedstock, 31% of product is obtained as viscous, dark oil.

Produced in the same way are:

1-Phenyl-1-(1-nitro-2-naphthylamino)-methanephosphonic acid diethylester

1-(1-nitro-2-naphthylamino)-ethane-1-phosphonic acid diethyl ester

1-(1-nitro-2-naphthylamino)-propane-1-phosphonic acid diethyl ester

1-(1-nitro-2-naphthylamino)-butane-1-phosphonic acid diethyl ester

c) (1-Amino-2-naphthylamino)-methanephosphonic acid diethyl ester

170 mg of (1-nitro-2-naphthylamino)-methanephosphonic acid diethyl esteris reduced in 2 ml of glacial acetic acid with 10 equivalents of ironpowder. After two hours, the mixture becomes viscous and then solid. Itis diluted with ethyl acetate, the iron is removed, and it ischromatographed with ethyl acetate. The product is obtained in 60%yield.

Produced in the same way are:

1-Phenyl-1-(1-amino-2-naphthylamino)-methanephosphonic acid diethylester

1-(1-amino-2-naphthylamino)-ethane-1-phosphonic acid diethyl ester

1-(1-amino-2-naphthylamino)-propane-1-phosphonic acid diethyl ester

1-(1-amino-2-naphthylamino)-butane-1-phosphonic acid diethyl ester

d) As described in Example 1, the amines are cyclized with oxalic acidderivatives to

1-Phenyl-1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanephosphonic acid diethyl ester

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-ethane-1-phosphonic acid diethyl ester

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-yl)-methanephosphonicacid diethyl ester

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-propane-1-phosphonic acid diethyl ester

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-butane-1-phosphonic acid diethyl ester

e) Nitration of the phosphonates leads to

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-ethane-1-phosphonic acid diethyl ester of meltingpoint >300° (decomposition)

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanephosphonic acid diethyl ester of melting point243° C.

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-propane-1-phosphonic acid diethyl ester

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-butane-1-phosphonic acid diethyl ester

1-phenyl-1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester

f) Saponification to phosphonic acids analogously to Example 1e).Obtained are

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-ethane-1-phosphonic acid of melting point >300°(decomposition) NMR(DMSO): 1.7 (3H d) 5.85 (1H), 7.8 (2H m), 8.5, 8.8,9.4 each 1H

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanephosphonic acid. NMR(DMSO): 4.7(2H d), 7.8 (2Hm), 8.5, 8.7, 8.8 each 1H

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-propane-1-phosphonic acid of melting point >300°(decomposition)

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-butane-1-phosphonic acid

1-phenyl-1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid

EXAMPLE 11

1-(6-Sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid is produced according toprocesses further described above fromamino-3-hydroxy-naphthalene-1-sulfonic acid.1-(6-Sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-ethane-1-phosphonic acid is synthesized analogously.

EXAMPLE 12

1-(8-Sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid is produced according toprocesses further described above from 6-hydroxy-naphthalene-2-sulfonicacid salt. 1-(8-Sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-ethane-1-phosphonic acid is synthesized analogously.

EXAMPLE 13

Analogously and with the methods usual for amino acids, by usingcommercially available amino acids and their derivatives, for example,tert-butyl esters, the following compounds are produced by way ofexample:

(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanecarboxylic acid

(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanecarboxylic acid

(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanecarboxylic acid

(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanecarboxylic acid

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-carboxylic acid

1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-carboxylic acid

1-(7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-carboxylic acid

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-ethane-1-carboxylic acid

EXAMPLE 14 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-acetonitrile

a) 1-Nitro-2-naphthylamino-acetonitrile

32.1 g of 1-aminoacetonitrile produced according to known specificationsis added to 21.58 g (80.7 mmol) of methanesulfonicacid-(1-nitronaphth-2-ol)-ester. It is stirred for 8 hours at 60°, thendiluted with dichloromethane and the mixture is applied to a columnfilled with silica gel. Chromatography with toluene yields, in additionto 7 g of 1-nitronaphth-2-ol, 13% of theory of(1-nitro-2-naphthylamino)-acetonitrile.

Obtained in the same way are:

(1-Nitro-2-naphthylamino)-methyl-acetonitrile

(1-nitro-2-naphthylamino)-1,1-dimethyl-acetonitrile.

b) (1-Amino-2-naphthyl)aminoacetonitrile

0.45 g of 1-nitro-2-naphthylamino-acetonitrile is hydrogenated at roomtemperature in 65 ml of dioxane on Pd/barium sulfate as catalyst. Afterremoval of the catalyst, 100% crude product of(1-amino-2-naphthyl)aminoacetonitrile is obtained.

Obtained analogously are:

(1-Amino-2-naphthylamino)-methyl-acetonitrile

(1-amino-2-naphthylamino)-1,1-dimethyl-acetonitrile

c) 1-(2,3-Dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-yl)-acetonitrile

0.41 g crude product of (1-amino-2-naphthyl)aminoacetonitrile is reactedanalogously to Example 1d) to 0.126 g of1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-yl)-acetonitrile. Themelting point is >350°. NMR(DMSO): 5.4 (2H), 7.55(2H), 7.75, 7.89, 8.03,8.63 each (1H d), 12.24 (1H s).

Obtained analogously are:

1-(2,3-Dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-yl)-methylacetonitrile

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-dimethyl-acetonitrile

d) 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-acetonitrile

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-yl)-acetonitrile isreacted with 65% nitric acid for 3 hours at room temperature. It isprecipitated from water, the yellow crystals are washed and 51% ofproduct of melting point >300° is obtained (slow decomposition).

Obtained analogously are:

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methylacetonitrile

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-dimethyl-acetonitrile

EXAMPLE 15 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanetetrazole and

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-yl)-methanetetrazole

301 mg of 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-acetonitrile is stirred for 2.5 hours at 150° in 12 mlof N-methylpyrrolidone with 3 equivalents of sodium azide as well as 1.5equivalents of triethylammonium chloride. After dilution andacidification of the cooled mixture, the crystals are suctioned off,washed with water and then acetonitrile and dried. 83% of1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-yl)-methanetetrazoleof melting point 320° results.

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanetetrazole is produced analogously to Example14d) from 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanetetrazole. Melting point >300°.

EXAMPLE 16 1-(2,3-Dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanecarboxylic acid-amidoxime

100 mg of 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-acetonitrile is refluxed for 4 hours with 2 equivalentsof hydroxylamine hydrochloride as well as sodium bicarbonate in 0.2 mlof water as well as a little ethanol. The product is precipitated afterdilution with water and suctioned off. Yield 62% NMR(DMSO): 4.9 (2H s),5.55 (2H s), 7.55 (3H m), 7.75, 7.95, 8.6 each 1H, 9.2OH, 12.2 (1Hbroad).

EXAMPLE 17 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetonitrile and1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetamide

In the same way as in Example 14a), there are obtained from thecorresponding methanesulfonic acid ester:

2-Nitro-1-naphthylamino-acetonitrile

(2-nitro-1-naphthylamino)-methyl-acetonitrile

(2-nitro-1-naphthylamino)-1,1-dimethyl-acetonitrile

Obtained analogously are:

(2-Amino-1-naphthylamino)-methyl-acetonitrile

(2-amino-1-naphthyl)aminoacetonitrile

(2-amino-1-naphthylamino)-1,1-dimethyl-acetonitrile

The compounds that are produced from them

1-(2,3-Dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-1-yl)-acetonitrile

NMR(DMSO): 5.2 (2H), 7.45, 7.53, 7.68, 7.83, 8.03, 8.14 each (1H d),12.2 (1H s).

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methylacetonitrile

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-dimethyl-acetonitrile

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetamide:

1-(2,3-Dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-1-yl)-acetonitrile isreacted with 65% nitric acid for 3 hours at room temperature. It isprecipitated from water, the yellow crystals are washed andapproximately 100% crude product is obtained of melting point >300°(slow decomposition). This is1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetamide.

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetonitrile results with use of nitroniumtetrafluoroborate and it melts at >300°.

Obtained analogously are:

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methylacetonitrile

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-dimethyl-acetonitrile

EXAMPLE 18

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanetetrazole (melting point 305°-315°decomposition) and

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo f!quinoxalin-1-yl)-methanetetrazole(melting point approximately 310° decomposition) are produced asdescribed in Example 15.

EXAMPLE 19 1-(2,3-Dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanecarboxylic acid-amidoxime

100 mg of 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-acetonitrile is refluxed for 7 hours with 2equivalents of hydroxylamine hydrochloride as well as sodium bicarbonatein 0.2 ml of water as well as a little ethanol. The product precipitatesafter dilution with water and is suctioned off. Yield 67%. NMR(DMSO):4.9 (2H s), 5.7 (2H s), 7.5 (3H m), 7.75, 7.95, 8.4 each 1H, 9.12OH,12.14 (1H broad).

EXAMPLE 20 6-(Piperidin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl!-methanephosphonic acid diethyl ester

A mixture of 100 microliters of aqueous glutaric dialdehyde (contentabout 25%), 300 microliters of diluted sulfuric acid and 1 ml oftetrahydrofuran/methanol 1:1 is added with stirring at ice bathtemperature to 37 mg of (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester in 2 ml oftetrahydrofuran z.A., to which 13 mg of sodium borohydride was added.Then, another 10 mg of sodium boronate is added and worked up for 1 morehour. The mixture is neutralized and extracted with ethyl acetate. Afterchromatography with a little silica gel, 16 mg of product is obtained.

After saponification of the ester, there is obtained

6-(Piperidin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl!-methanephosphonic acid.

Synthesized analogously are:

6-(Piperidin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-methanephosphonic acid diethyl ester as well as

6-(piperidin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-methanephosphonic acid.

EXAMPLE 21 6-(Morpholin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl!-methanephosphonic acid

6-(Morpholin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl!-methanephosphonic acid diethyl ester is obtained from(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid diethyl ester according to themethod by reaction with 3-oxa-glutaric acid dialdehyde that is describedin Example 20. With the usual method, there is obtained

6-(Morpholin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl!-methanephosphonic acid.

Obtained analogously are:

6-(Morpholin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-methanephosphonic acid diethyl ester as well as

6-(Morpholin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-methanephosphonic acid and

1- 6-(morpholin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-ethanephosphonic acid diethyl ester as well as

1- 6-(morpholin-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-ethanephosphonic acid.

EXAMPLE 22

1- 6-(Imidazolyl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-ethanephosphonic acid diethyl ester or 1-6-(imidazolyl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-ethanephosphonic acid are produced by nucleophilicaromatic substitution from the halogen derivatives with imidazole asnucleophile.

Also, there are produced

6-(Imidazolyl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-methanephosphonic acid diethyl ester

6-(imidazolyl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl!-methanephosphonic acid

6-(imidazolyl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl!-methanephosphonic acid diethyl ester

6-(imidazolyl)-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl!-methanephosphonic acid.

We claim:
 1. A benzo f!quinoxalinedione compound of formula I ##STR6##in which R¹ and R⁴ are the same or different and mean hydrogen, C₁₋₁₂alkyl substituted with R², C₂₋₁₂ alkenyl substituted with R², C₂₋₁₂alkynyl substituted with R², C₃₋₇ cycloalkyl substituted with R²,--(CH₂)_(n) --C₆₋₁₂ aryl, which is substituted with R² in the aryl or inthe alkyl radical or --(CH₂)_(n) -hetaryl, which is substituted with R²in the hetaryl or alkyl radical, and R¹ and R⁴ do not mean hydrogen atthe same time,R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are the same or different andmean hydrogen, halogen, nitro, NR¹⁶ R¹⁷, NHCOR¹¹, SO₀₋₃ R¹², C₃₋₇cycloalkyloxy, COR¹³, cyano, CF₃, OCH₂ CF₃, C₁₋₆ alkyl or C₁₋₆ alkoxy,and R² is --CN, -tetrazole, --C(NOH)NH2, --CO--R³ or --PO-XY and R² isthe same or different in one to two places, and n is 0, 1, 2, 3, 4 or 5,R³ means hydroxy, C₁₋₆ alkoxy or NR¹⁴ R¹⁵, X and Y are the same ordifferent and mean hydroxy, C₁₋₆ alkoxy, --O--(CH₂)_(p) --O--, C₁₋₄alkyl or NR¹⁴ R¹⁵ and p is 1, 2 or 3 and R¹¹ means C₁₋₆ alkyl or phenyl,which can be substituted with halogen, R¹² means hydrogen, C₁₋₄ alkyl,NH₂, N(C₁₋₄ alkyl)₂, --NH(C₁₋₄ alkyl), --NH--CH₂ CONH₂, --CH₂ CONH₂, CF₃or --NH--(CH₂)_(n) --R² and R¹³ means hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylor NR¹⁴ R¹⁵, R¹⁴ and R¹⁵, R¹⁶ and R¹⁷ are the same or different and meanhydrogen, --CO--C₁₋₆ alkyl, phenyl or C₁₋₆ alkyl, which can beoptionally substituted with C₁₋₄ alkoxy or with an amino groupoptionally mono- or disubstituted with C₁₋₄ alkyl or together with thenitrogen atom can form a 5- to 7-membered saturated heterocycle, whichcan contain another N, S or O atom and can be substituted or can form anunsaturated 5-membered heterocycle, which can contain 1-3N atoms and canbe substituted, as well as their isomers or salts, and, if R⁵ -R¹⁰ ishydrogen, R¹ or R⁴ does not mean methanephosphonic acid orethane-1-phosphonic acid.
 2. (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonicacid(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid(6-nitro-7-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid(6-nitro-8-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid(6-nitro-8-sulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid(6-nitro-8,10-disulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanephosphonic acid(6-nitro-8,10-disulfonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-4-yl)-methanephosphonic acid(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanecarboxylic acid(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-methanecarboxylic acid(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanecarboxylic acid1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-carboxylic acid1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-1-yl)-ethane-1-carboxylic acid1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-ethane-1-carboxylic acid(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzof!quinoxalin-yl)-methanephosphonic acid.
 3. A method for treatment of adisease caused by hyperactivity of excitatory amino acids whichcomprises administering an effective amount of a compound according toclaim
 1. 4. A process for the production of a compound of formula Iaccording to claim 1, which comprises:a) cyclizing a compound of formulaII or III ##STR7## with oxalic acid or a reactive oxalic acid derivativeor b) reacting a compound of formula IV or V ##STR8## with oxalic acidor a reactive oxalic acid derivative and after reduction of the nitrogroup cyclizing the resultant compound or c) reacting a compound offormula VI ##STR9## in the presence of a base, with R¹ Z or R⁴ Z, inwhich Z represents a leaving group, and then optionally saponifying theester group or esterifying or amidating the acid group or reducing thenitro group to the amino group or alkylating or acylating the aminogroup or exchanging the amino group for halogen or cyano or introducinga nitro group or halogen or converting or nucleophilically substitutinga nitrile into the tetrazole or amidoxime or separating the isomers orforming the salts.
 5. A pharmaceutical composition comprising apharmaceutically effective amount of a compound according to claim
 1. 6.A compound according to claim 1, wherein R² is --COR³ or --PO-XY and oneor both of R¹ and R⁴ are alkyl substituted with R².
 7. The method ofclaim 3, wherein the compound is administered in a daily dose of 5 to200 mg.
 8. The method of claim 3, wherein the disease is aneurodegenerative disorder, postischemic cell destruction, celldestruction after cerebral trauma, senile dementia, multi-infarctdementia, epilepsy or muscle spasms.
 9. The method of claim 3, whereinthe disease is anxiety, schizophrenia, migraine, pain, a sleep disorderor drug withdrawal.
 10. The method of claim 3, wherein the compound isadministered in a daily dose of 0.5 to 1000 mg.